1 / 65

Hemostasis & Thrombosis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006

Hemostasis & Thrombosis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006. HEMOSTASIS. Hemorrhage. Thrombosis. Hemostasis. HEMOSTASIS (CONT.). 1). INITIATION Vessel wall – endothelial cells and subendothelial components 2). LOCALIZATION

Download Presentation

Hemostasis & Thrombosis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Hemostasis & Thrombosis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006

  2. HEMOSTASIS Hemorrhage Thrombosis Hemostasis

  3. HEMOSTASIS (CONT.) 1). INITIATION Vessel wall – endothelial cells and subendothelial components 2). LOCALIZATION Platelets – circulating cellular elements 3). PROPAGATION/AMPLIFICATION Plasma coagulation proteins (factors) 4). TERMINATION Plasma coagulation protein inhibitors 5). ELIMINATION Fibrinolytic system

  4. Vessel Wall: Endothelial cells

  5. Antithrombotic Attributes of Vascular Endothelium

  6. Vessel Wall (cont.)

  7. Response to Vessel Wall Injury: Platelet adhesion • Exposure of flowing blood and platelets to subendothelial components • Platelets bind to the subendothelial collagen bound tovon Willebrand factor (vWF), which is secreted from endothelial cells directly into the subendothelial space or adsorbed from plasma following endothelial cell secretion • vWf also binds directly to platelets via glycoprotein Ib-IX

  8. PLATELETS

  9. Platelets adhered to damaged endothelium

  10. Platelet Plug Formation = 1° hemostasis

  11. Platelet Plug Formation: Platelet activation • Activated via their interaction with subendothelial collagen • Additional platelet agonists include ADP, epinephrine, thrombin, immune complexes, and high shear stress – all of the compounds interact with specific platelet membrane receptors • Several platelet activation pathways are initiated

  12. Platelet Plug Formation: Platelet activation events • Platelet shape change: extend pseudopodia, which facilitates aggregation and coagulant activity • Release of alpha and dense granule contents including a number of compounds involved in hemostasis (eg ADP, factor V and fibrinogen) • Aggregation

  13. Response to Vessel Wall Injury: Vasoconstriction • Temporarily reduces local blood flow and hence, blood loss • Mediated in part by serotonin and thromboxane A2 (TXA2) from activated platelets Serotonin is released from platelet dense granules TXA2 is a product of platelet prostaglandin metabolism

  14. Activated platelets

  15. Platelet Plug Formation: Platelet aggregation • Platelet activation results in the functional expression of membrane receptors normally expressed in a non-functional state (glycoprotein IIb-IIIa) • Fibrinogen from the plasma or released from activated platelet alpha-granules binds to activated glycoprotein IIb-IIIa membrane receptors effectively bridging platelets to each other

  16. Platelets adhered to and aggregated upon collagen

  17. Platelet Plug Formation

  18. HEMOSTASIS 1). INITIATION Vessel wall – endothelial cells and subendothelial components 2). LOCALIZATION Platelets – circulating cellular elements 3). PROPAGATION/AMPLIFICATION Plasma coagulation proteins (factors) 4). TERMINATION Plasma coagulation protein inhibitors 5). ELIMINATION Fibrinolytic system

  19. BLOOD COAGULATION

  20. BLOOD COAGULATION (CONT.) • Deficiencies in all of the factors, except factor XII, lead to a bleeding tendency in the affected individual • Described as a ‘waterfall’ or ‘cascade’ sequence of zymogen (pro-enzyme) to enzyme conversions, with each enzyme activating the next zymogen in the seqeunce • Activated factor enzymes are designated with an “a”, e.g. factor Xa

  21. Common constituents of coagulation complexes Vitamin K-dependent (VKD) zymogen Ca2+ Protein cofactor Appropriate membrane surface - activated platelets (VIIIa/IXa complex, Va/Xa complex) • subendothelial cells, typically fibroblasts (TF/VIIa complex)

  22. Common constituents of coagulation complexes Vitamin K-dependent (VKD) zymogen Ca2+ Protein cofactor Appropriate membrane surface - activated platelets (VIIIa/IXa complex, Va/Xa complex) • subendothelial cells, typically fibroblasts (TF/VIIa complex)

  23. Functional Domains of the Vitamin K- dependent Zymogens

  24. Gamma (g)-carboxyglutamic acid

  25. Formation of Gla residues subsequent to protein synthesis (post-translational) H2 • Group of related, fat soluble compounds, which differ in the number of side-chain isoprenoid units • Plant derived (vitamin K1) and synthesized by intestinal bacteria (vitamin K2)

  26. Common constituents of coagulation complexes Vitamin K-dependent (VKD) zymogen Ca2+ Protein cofactor Appropriate membrane surface - activated platelets (VIIIa/IXa complex, Va/Xa complex) • subendothelial cells, typically fibroblasts (TF/VIIa complex)

  27. Relative Rate of Prothrombin Activation Prothrombinase Components -Thrombin Prothrombin 1 FXa FXa Ca2+ FVa HC 300 FXa Ca2+ Ca2+ FVa LC FXa Ca2+ 30 Ca2+ Prothrombinase FXa 300,000 Ca2+ FVa HC FVa HC Ca2+ FVa LC FVa LC Relevance of complex formation and its constituents

  28. Common constituents of coagulation complexes Vitamin K-dependent (VKD) zymogen Ca2+ Protein cofactor Appropriate membrane surface - activated platelets (VIIIa/IXa complex, Va/Xa complex) • subendothelial cells, typically fibroblasts (TF/VIIa complex) ** Express anionic phospholipids and membrane receptors for coagulation proteins. In platelets, the expression of this membrane surface is activation-dependent.

  29. Activate platelets

  30. HEMOSTASIS (CONT.) 1). INITIATION Vessel wall – endothelial cells and subendothelial components 2). LOCALIZATION Platelets – circulating cellular elements 3). PROPAGATION/AMPLIFICATION Plasma coagulation proteins (factors) 4). TERMINATION Plasma coagulation protein inhibitors 5). ELIMINATION Fibrinolytic system

  31. INHIBITORS

  32. INHIBITORS (cont.)

  33. FIBRINOLYSIS

  34. FIBRINOLYSIS (CONT.)

  35. Platelet Plug Formation • Measured clinically as the bleeding time • Normal bleeding time is from 2 – 10 min • Usually the bleeding time is sufficient to detect defects of platelet adhesion and aggregation, in which it is prolonged

  36. Intrinsic Pathway of Blood Coagulation • No factors extrinsic to the blood are involved • Clinical test to assess the functionality of this pathway is the activated partial thromboplastin time (aPTT) • Kaolin and cephalin are added to the test plasma sample • The normal range is ~30 – 50 seconds (varies slightly depending on the laboratory) • Prolongations in the aPTT are observed in deficiencies of factors XI, IX, VIII, X, and V, prothrombin, or fibrinogen. • Used to test for common congenital hemophilias (deficiencies in IX, VIII, or XI) and to monitor heparin treatment

  37. Extrinsic Pathway of Blood Coagulation • Extrinsic refers to tissue factor, which is expressed on subendothelial cells • Clinical test to assess the functionality of this pathway is the prothrombin time (PT) • Lipidated tissue factor is added to test plasma sample • The normal range is ~10-15 seconds (varies slightly depending on the laboratory) • Prolongations in the PT are observed in deficiencies of factors VII, X, V, prothrombin, or fibrinogen. • Used to test for the rare congenital deficiencies in these factors: More often it is used to diagnose acquired bleeding disorders resulting from vitamin K deficiency, oral anticoagulants (e.g. warfarin), and liver disease

  38. Thrombin Time (TT) In this test, thrombin is added to plasma • The normal range is ~10-15 seconds (varies slightly depending on the laboratory) • Prolongations in the TT are observed in congenital fibrinogen deficiency or acquired fibrinogen deficiency resulting from consumption of fibrinogen in DIC (disseminated intravascular coagulation), or may occur following treatment with fibrinolytic drugs

  39. Hemorrhage Bleeding disorders can span the spectrum from weeping blood vessels to full-fledged internal and external hemorrhage Genetic defects: platelet abnormalities blood vessel wall abnormalities clotting factor deficiencies (hemophilias) excess clot breakdown (fibrinolysis) Acquired defects: liver disease (site of clotting factor synthesis) vitamin K deficiency autoimmune disease (platelet destruction) trauma

  40. Disorders of Platelet Adhesion or Aggregation • Affecting constituents of the vessel wall • Affecting the ability of the platelet to interact with the subendothelium at sites of blood vessel injury • Affecting the ability of the platelet to interact with other platelets

  41. Vessel Wall Defects • von Willebrand’s disease: a group of autosomal dominant disorders that result in reduced or abnormal synthesis of vWF • Defects in collagen synthesis Ehlers-Danlos Syndrome: congenital defect in collagen synthesis Scurvy: results from vitamin C (ascorbic acid) deficiency, which is involved in collagen synthesis Excess exogenous or endogenous corticosteroids: also leads to acquired deficiency in collagen synthesis

  42. Platelet Defects • Bernard-Soulier Syndrome: expression of low levels of or defective glycoprotein Ib-IX on the platelet surface • Glanzmann’s thrombasthenia: expression of low levels of or defective glycoprotein IIb-IIIa on the platelet surface

More Related